Note: Descriptions are shown in the official language in which they were submitted.
CA 02375234 2001-12-21
PCT/EP99/04325
G 2702-PCT As amended by submission of 21.06.2001
1
Process for the separation of the diastereomeric bases of
2-[(dimethylamino)methyl]-1-(3-methoxyphenyl)cyclohexanol
This invention relates to a process for the purification
and separation of the diastereomers of 2-[(dimethylamino)-
methyl]-1-(3-methoxyphenyl)cyclohexanol.
This compound and the salts thereof are of pharmaceutical
interest. Tramadol hydrochloride, CA no. 36282-47-0 (~)-
trans-2-[(dimethylamino)methyl]-1-(3-methoxyphenyl)cyclo-
hexanol hydrochloride has long been commercially available
as a highly effective analgesic.
The above designation of the cis/trans isomers is not in
accordance with IUPAC nomenclature. Compound CA no. 36282-
47-0 is accordingly hereinafter designated the cis isomer
or cis-tramadol in accordance with IUPAC nomenclature and
taken to encompass the racemic mixture of (1R,2R)- and
(1S,2S)-2-[(dimethylamino)methyl]-1-(3-methoxyphenyl)cyclo-
hexano1, while the racemic mixture of (1R,2S)- and (1S,2R)-
2-[(dimethylamino)methyl]-1-(3-methoxyphenyl)cyclohexanol
is designated the trans isomer or trans-tramadol.
Known purification and separation processes, US 3,830,934
and DE-OS 4 330 240, for the above-stated tramadol
hydrochloride are based on the reaction of the
diastereoisomeric base mixture with mineral acids and
subsequent fractional crystallisation from organic
solvents. The disadvantage of this procedure is that it
gives rise to two or more fractions which require further
processing, so greatly reducing economic viability.
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Moreover, since concentrated mineral acids are sometimes
used, this procedure inevitably gives rise to decomposition
products due to the acid lability of the tertiary alcohol
function. Furthermore, separation of the cis/trans isomers
may only be achieved by means of the above-stated process
if the isomer ratio of the base mixture to be separated is
greater than 75:25 cis:trans.
WO 99/03820 describes a process for the production of pure
cis-tramadol hydrochloride, in which a monohydrate of the
corresponding cis-tramadol base is obtained from the
Grignard bases by addition of water and is separated.
In all hitherto known processes, the trans:trans isomer
ratio of the diastereomeric base mixtures to be separated
is 80:20 and above. For example, according to DE-OS
4 330 240 or US 5,414,129, the ratio is 86:14.
However, there is also interest in separating the desired
cis isomer from mixtures which contain the diastereomeric
bases in an unfavourable isomer ratio, in order, for
example, to be able to work up Grignard reaction mixtures
obtained from deviant reaction conditions or also mother
liquors. Mother liquors arising from a first precipitation
of the desired isomer still contain the diastereomeric
bases in a cis:trans isomer ratio of approx. 50:50.
The object of the invention is accordingly to provide a
process which, without primary salt formation, permits
separation of the diastereomers from a diastereomeric base
mixture of 2-[(dimethylamino)methyl]-1-(3-methoxyphenyl)-
cyclohexanol over a wide isomer ratio range.
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G 2702-PCT As amended by submission of 21.06.2001
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' It has surprisingly been found that diastereomer separation
with 2-[(dimethylamino)methyl]-I-(3-methoxyphenyl)cyclo-
hexanol advantageously proceeds by formation of a base
hydrate by adding water or preferably organic solvent or
solvent mixture and water to a diastereomeric base mixture
of this compound with a cis:trans isomer ratio of below
80:20.
The invention accordingly provides a process for the
separation of the diastereomeric bases of 2-[(dimethyl-
amino)methyl]-1-(3-methoxyphenyl)cyclohexanol by treatment
with water in at least stoichiometric quantities for
complete conversion of the bases and subsequent separation
of the precipitated hydrate of the cis diastereomer, which
process is characterised in that a base mixture with a
cis:trans isomer ratio of below 80:20, preferably of 60:40-
75:25, is used.
When separating contaminated diastereomeric base mixtures,
said mixtures are preferably dissolved in a water-miscible
organic solvent or solvent mixture before the reaction with
water, wherein solvents from the group of alcohols,
ketones, esters, ethers, low molecular weight polyalcohols
or aromatic hydrocarbons are used. The organic solvent or
solvent mixture is here preferably used in a volume ratio
to water of 10:2-10:5.
The water-miscible organic solvents used are preferably C1_8
alcohols, C3_$ ketones, CZ_$ esters, aliphatic, aromatic,
open-chain and cyclic C9_$ ethers, CZ_6 polyalcohols or C5_g
aromatics.
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' The separated hydrate crystals of the cis diastereomer are
finally washed with a mixture of the organic solvent and
water in a volume ratio of 10:2-10:5 and then dried.
The water is used in at least stoichiometric quantities far
complete conversion of the bases. Moreover, the water and
also the solvent or solvent mixture may be used with the
diastereomeric base mixture in a wide range of mixing
ratios.
Separation of the diastereomers may proceed over a wide
temperature range, provided that it is ensured that the
reaction mixture does not freeze out at low temperatures.
At higher temperatures, the temperature of the reaction
mixture is preferably maintained below the melting point of
the base hydrate.
The process according to the invention is characterised in
that, under the described conditions, the diastereomeric
base mixture forms a hydrate and this hydrate, namely the
cis diastereomer, preferably precipitates, so enabling easy
separation of the diastereomers.
In comparison with hitherto described procedures, the
process offers the advantages that diastereomer separation
may proceed without salt formation (for example via the
hydrochloride), that unwanted decomposition products are
simply and effectively avoided by the formation of the base
hydrate and that subsequent salt formation with numerous
acids is possible directly via the base stage. Above all,
however, the process makes it possible to separate
CA 02375234 2001-12-21
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G 2702-PCT As amended by submission of 21.06.2001
diastereomeric base mixtures, the cis:trans isomer ratio of
which deviates greatly from that conventionally arising
after the Grignard reaction. In particular, the process is
suitable for working up mother liquors.
5
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Examples
Example 1
50 g of a diastereomeric base mixture of (~)-cis/trans-2-
[(dimethylamino)methyl]-1-(3-methoxyphenyl)cyclohexanol
(cis:trans isomer ratio = 75:25) were dissolved in 100 ml
of acetone. 20 ml of water were then added and the reaction
mixture stirred at 20°C. Crystallisation began after
approx. 30 minutes. The suspension was stirred for a
further 90 minutes. The crystals were separated from the
mother liquor using a filter, were washed twice with an
acetone/water mixture (volume ratio 10:2) and suction
filtered dry. The hydrate of the cis diastereomer was
obtained at a yield of 67% and a purity of greater than
950. The isomer ratio in the crystal fraction was 98% cis
isomer to 2o traps isomer.
Example 2
50 g of a diastereomeric base mixture of (~)-cis/trans-2-
[(dimethylamino)methyl]-1-(3-methoxyphenyl)cyclohexanol
(cis:trans isomer ratio = 75:25) were dissolved in 100 ml
of isopropanol. 50 ml of water were then added and the
reaction mixture stirred at 45°C. Crystallisation began
after approx. 20 minutes. The suspension was stirred for a
further 90 minutes. The crystals were separated from the
mother liquor using a filter, were washed twice with an
isopropanol/water mixture (volume ratio 10:5) and suction
filtered dry. The hydrate of the cis diastereomer was
obtained at a yield of 64°s and a purity of greater than
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- 95%. The isomer ratio in the crystal fraction was 97% cis
isomer to 3% trans isomer.
Example 3
50 g of a diastereomeric base mixture of (~)-cis/trans-2-
[(dimethylamino)methyl]-1-(3-methoxyphenyl)cyclohexanol
(cis:trans isomer ratio = 75:25) were dissolved in 50 ml of
tetrahydrofuran (THF). 25 ml of water were then added and
the reaction mixture stirred at 0°C. Crystallisation began
overnight. The suspension was stirred for a further 90
minutes. The crystals were separated from the mother liquor
using a filter, were washed twice with an THF/water mixture
(volume ratio 10:5) and suction filtered dry. The hydrate
of the cis diastereomer was obtained at a yield of 66% and
a purity of greater than 950. The isomer ratio in the
crystal fraction was 98o cis isomer to 2°s trans isomer.
Example 4
100 g of a diastereomeric base mixture of (~)-cis/trans-2-
[(dimethylamino)methyl]-1-(3-methoxyphenyl)cyclohexanol
(cis:trans isomer ratio = 75:25) were exposed to
atmospheric humidity. After 3 days, a crystalline mass was
obtained, which, after washing three times with cold
ethanol/water, gave rise to the hydrate of the cis
diastereomer at a yield of 45o and a purity of 95s. The
isomer ratio in the crystal fraction was 98.1 cis isomer
to 1.9o traps isomer.
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G 2702-PCT As amended by submission of 21.06.2001
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- Example 5
Conversion of a base hydrate obtained according to the
invention into a salt:
20 g of the moist crystallisate obtained according to
Example 1 were dissolved in 40 ml of isopropanol and
stirred together with 36o hydrochloric acid until the
measured pH value of the solution fell below 3. The solvent
was then stripped out and the product recrystallised from
isopropanol. Tramadol hydrochloride was obtained.
Example 6
50 g of a diastereomeric base mixture of (~)-cis/trans-2-
[(dimethylamino)methyl]-1-(3-methoxyphenyl)cyclohexanol
(cis:trans isomer ratio = 63:37) were dissolved in 100 ml
of acetone. 20 ml of water were then added and the reaction
mixture stirred at 20°C. Crystallisation began after
approx. 30 minutes. The suspension was stirred for a
further 90 minutes. The crystals were separated from the
mother liquor using a filter, were washed twice with an
acetone/water mixture (volume ratio 10:2) and suction
filtered dry. The hydrate of the cis diastereomer was
obtained at a yield of 36o and a purity of greater than
95%. The isomer ratio in the crystal fraction was 97% cis
isomer to 3o trans isomer.
Example 7
20 g of a diastereomeric base mixture of (~)-cis/trans-2-
[(dimethylamino)methyl]-1-(3-methoxyphenyl)cyclohexanol
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- (cis:trans isomer ratio = 75:25) were dissolved in 20 g of
ethanol at 22°C and combined with 20 vol.% of water. The
solution was cooled to 6°C and left to stand for 6 hours.
The resultant crystals were removed by suction filtration
and washed twice with 10 ml portions of ethanol/water.
After drying, the hydrate of the cis diastereomer is
obtained at a yield of 34~ and a purity of greater than
95%. The isomer ratio in the crystal fraction was 98.80 cis
isomer to 1.2o traps isomer.
Example 8
g of a diastereomeric base mixture of (~)-cis/trans-2-
[(dimethylamino)methyl]-1-(3-methoxyphenyl)cyclohexanol
15 (cis:trans isomer ratio = 75:25) were dissolved in 20 g of
ethanol at 22°C and combined with 33 vol.o of water. The
solution was cooled to 6°C and left to stand for 6 hours.
The resultant crystals were removed by suction filtration
and washed twice with 10 m1 portions of ethanol/water.
20 After drying, the hydrate of the cis diastereomer is
obtained at a yield of 43% and a purity of greater than
95s. The isomer ratio in the crystal fraction was 99.40 cis
isomer to 0.6o traps isomer.
Example 9
20 g of a diastereomeric base mixture of (~)-cis/trans-2-
[(dimethylamino)methyl]-1-(3-methoxyphenyl)cyclohexanol
(cis:trans isomer ratio = 75:25) were dissolved in 20 g of
ethanol at 22°C and combined with 40 vol.~ of water. The
solution was cooled to 6°C and left to stand for 6 hours.
The resultant crystals were removed by suction filtration
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G 2702-PCT As amended by submission of 21.06.2001
' and washed twice with 10 ml portions of ethanol/water.
After drying, the hydrate of the cis diastereomer is
obtained at a yield of 46o and a purity of greater than
95%. The isomer ratio in the crystal fraction was 99.80 cis
5 isomer to 0.2% trans isomer.
Example 10
g of a diastereomeric base mixture of (~)-cis/trans-2-
10 [(dimethylamino)methyl)-1-(3-methoxyphenyl)cyclohexanol
(cis:trans isomer ratio = 75:25) were dissolved in 20 g of
ethanol at 22°C and combined with 50 vol.% of water. The
solution was cooled to 6°C and left to stand for 6 hours.
The resultant crystals were removed by suction filtration
15 and washed twice with 10 ml portions of ethanol/water.
After drying, the hydrate of the cis diastereomer is
obtained at a yield of 50% and a purity of greater than
95%. The isomer ratio in the crystal fraction was 99.50 cis
isomer to 0.5o traps isomer.
Example 11
20 g of a diastereomeric base mixture of (~)-cis/trans-2-
[(dimethylamino)methyl)-1-(3-methoxyphenyl)cyclohexanol
(trans:cis isomer ratio = 75:25) were dissolved in 20 g of
ethanol at 22°C and combined with 60 vol.% of water. The
solution was cooled to 6°C and left to stand for 6 hours.
The resultant crystals were removed by suction filtration
and washed twice with 10 m1 portions of ethanol/water.
After drying, the hydrate of the cis diastereomer is
obtained at a yield of 53% and a purity of greater than
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- 950. The isomer ratio in the crystal fraction was 99.60 cis
isomer to 0.4o trans isomer.
